Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer's disease-associated genes: DTNB and DLG2

Abstract

Alzheimers disease (AD) is a genetically complex disease for which roughly 30 genes have been identified via genome-wide association studies. We attempted to identify rare variants (minor allele frequency <0.01) associated with AD in a region-based, whole genome sequencing (WGS) association study (GSAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved p-values < 10-6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden test and replicated in case/control samples from the ADSP study (pmeta = 4.74x10-8). SKAT analysis revealed region-based association around the discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta =1x10-6). Here, in a region-based GSAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.